ABSTRACT Today, there is a fascination with gut-to-brain sensory transduction. Nutrients and bacteria are known to modulate behaviors. However, how the brain modulates gastrointestinal sensory function is unknown. Several behavioral disorders, such as those related to stress and appetite, have been linked with altered visceral function. The pillars of sensory transduction in the gut are the neurons that innervate the mucosa and the enteroendocrine cells ? epithelial cells that face the lumen. When stimulated by nutrients, or bacteria, they fire action potentials. We recently discovered that these cells synapse with the vagus nerve to transduce nutrient stimuli to the brain in milliseconds. They do so using glutamate as a neurotransmitter. Recent studies have also shown that a subset of enteroendocrine cells that secrete serotonin are activated by the sympathetic neurotransmitter, norepinephrine. Our preliminary data show that these cells also receive synaptic inputs from peripheral neurons of the spinal cord. Therefore, we hypothesize that spinal neurons use norepinephrine as an efferent neurotransmitter to modulate enteroendocrine cell sensory function. With the support of this NIH R21 research project, our goal is to dissect this neural circuit by 1) defining the efferent synapse both in vivo and in vitro; and 2) establishing norepinephrine as an efferent neuron-to-enteroendocrine cell synaptic neurotransmitter. This project will set the neural basis for understanding how brain function and behaviors alter visceral sensory function.